Method for promoting ovulation, parturition, and lactation in mammals

ABSTRACT

The present invention generally relates to various methods for promoting ovulation, parturition and lactation in female mammals. These benefits are obtained by administering to the mammals a composition containing a D2 receptor antagonist that does not substantially cross the blood brain barrier. In one embodiment, the D2 receptor antagonist is domperidone. The domperidone can be administered to the mammal either orally or subcutaneously and can be used to treat, for instance, anestrous mammals, mammals that have problems bearing offspring and mammals suffering from agalactia. Unexpectedly, it has also been discovered that the D2 receptor antagonist may also stimulate feed intake, causing the mammal to eat more and gain weight faster.

RELATED APPLICATION

This application is a divisional of prior application Ser. No.08/768,981, filed on Dec. 18, 1996, which issued as U.S. Pat. No.6,224,895.

FIELD OF THE INVENTION

The present invention generally relates to a method for promotingovulation, parturition and lactation in female mammals. Moreparticularly, the present invention is directed to a method ofadministering a dopamine D₂ receptor antagonist, such as domperidone, toa female mammal for altering hormonal levels in the animal in order topromote ovulation, parturition or lactation.

BACKGROUND OF THE INVENTION

Breeders of various animals, such as horses and other livestock, facemany problems in getting the animals to breed properly. For instance,some female mammals fail to ovulate and fall into heat in regularintervals. Mammals that exhibit a prolonged period of inactivity betweentwo periods of heat are described as being anestrous. Anestrous femalemammals will not accept the male and are incapable of conceivingoffspring.

Another problem breeders experience is the inability of some mammals toprepare for and give birth after the mammals have become pregnant andthe fetus is ready to be born. In preparation for and during the act ofgiving birth, a process known as parturition, the pregnant mammal shouldexperience cervical relaxation, swelling of the vulva, and relaxation ofligaments around the pelvis. Without these events occurring, the mammalis not capable of giving natural, unassisted birth. Further, shouldthese events not occur, the health of the mother and of the unbornoffspring are at grave risk.

Another problem commonly experienced by breeders is the inability ofmammals to produce and secrete milk after giving birth. The condition offailing to lactate properly after child birth is referred to asagalactia, and is especially prevalent in mares and other livestock.Should the mammal not lactate properly, the offspring must then bebottle fed which is time consuming, labor intensive, and significantlyadds to the cost of raising the livestock.

Each of the problems mentioned above can be caused to a great extent byhormonal imbalance or by hormonal irregularities. Hormones released inthe body are primarily responsible for initiating ovulation,parturition, and lactation in mammals. Thus, if hormones are notreleased in the body at particular critical times, the above describedproblems can be experienced.

For instance, hormones can be prevented from being released in the bodyby various chemical agents. One such known chemical agent is dopamine.Dopamine is a decarboxylated form of dopa. Dopamine is believed to beproduced by the body when it is necessary to suppress hormone secretion.Dopamine suppresses hormone release by binding to and tying up receptorson the anterior pituitary, an endocrine gland located at the base of thebrain not far from the hypothalamus. By binding to the anteriorpituitary, the gland is prevented from receiving a stimulus hormone thatcauses it to release other hormones such as those necessary forovulation, parturition, and lactation.

Although dopamine is necessary during particular periods for keepinghormone levels in the body within controlled ranges, excess levels ofdopamine can adversely interfere with the process of reproduction. Also,besides dopamine, there are other chemical agents that can interferewith or prevent hormone secretion, adversely affecting biologicalprocesses.

Thus, a need exists for a method of promoting follicular growth andovulation, parturition, and lactation in female mammals. A need alsoexists for treating anestrous mammals, agalactic mammals, and mammalsthat fail to prepare for parturition when a fetus is ready to be born. Afurther need exists for a chemical agent that antagonizes dopamine andother chemicals that act in a similar manner in order to counteracthormonal imbalance and irregularities.

SUMMARY OF THE INVENTION

The present invention recognizes and addresses the foregoingdisadvantages, and others of prior art constructions and methods.

Accordingly, it is an object of the present invention to provide aprocess for promoting ovulation and for treating anestrous mammals.

Another object of the present invention is to provide a method forpromoting parturition in a pregnant mammal that is at the end of thepregnancy cycle.

It is another object of the present invention to provide a process forpromoting lactation and for treating agalactia in mammals that have justgiven birth.

Still another object of the present invention is to provide a processfor controlling hormonal release in the body.

Another object of the present invention is to provide a method foraltering hormone levels in the body of a mammal by administering to themammal a dopamine antagonist.

It is another object of the present invention to provide a process fortreating a mammal that has excess levels of dopamine and other similaracting agents within its body.

These and other objects of the present invention are achieved byproviding a method for promoting follicular growth and ovulation, forpreparing a mammal for parturition, and for promoting lactation byadministering to a female mammal a composition. The composition containsa dopamine D₂ receptor antagonist. For instance, in one embodiment, thecomposition can contain domperidone.

The present inventor has used domperidone in the past for treatinganimals suffering from fescue toxicosis. For instance, the presentinventor's prior work is disclosed in U.S. Pat. No. 5,372,818 entitled“Method of Treating Fescue Toxicosis with Domperidone”, which isincorporated herein by reference in its entirety. In U.S. Pat. No.5,372,818, it was discovered not only that domperidone is an effectiveagent for treating fescue toxicosis, but that domperidone does notsubstantially cross the blood brain barrier. Therefore, domperidone canbe administered to animals while avoiding substantial adverse behavioraland neurological side effects. Such neuroleptic side effects have beenobserved in animals exposed to other D₂ receptor antagonists such as thedrugs, metoclopramide and sulpiride.

Although U.S. Pat. No. 5,372,818 provides great advances in the art fortreating animals infected with fescue toxicosis, various advantages,aspects and features of the present invention remain absent from thepresent inventor's prior patent.

According to the present invention, ovulation, parturition or lactationcan be promoted by administering to a mammal a composition containing adopamine D₂ receptor antagonist, such as domperidone. The D₂ receptorantagonist can be administered to the mammal in an amount from about0.08 mg to about 3.3 mg per kilogram of body weight of the mammal. TheD₂ receptor antagonist can be administered to the mammal either orallyor subcutaneously.

Specifically, when using domperidone to promote follicular growth andovulation, domperidone can be orally administered at a concentration offrom about 0.2 mg to about 3.3 mg per kilogram weight of said mammal. Inone preferred embodiment, the dosage of domperidone is about 0.55 mg perkilogram weight of the mammal.

When administered subcutaneously, the dosage can be from about 0.08 mgto about 1.32 mg and particularly around 0.22 mg per kilogram weight ofthe mammal.

When attempting to promote parturition, udder development, andlactation, on the other hand, domperidone can be administered orally toa mammal at a dosage of from about 0.2 mg to about 3.3 mg andparticularly at about 1.1 mg per kilogram weight of the mammal. Whenadministered subcutaneously, the dosage of domperidone can be from about0.08 mg to about 1.32 mg and particularly at about 0.44 mg per kilogramweight of the mammal.

All of the above dosage levels according to the present invention can begiven daily. Although unknown, it is believed that the treatments causehormonal levels in the mammal to change for promoting either ovulation,parturition or lactation. Unexpectedly, it has also been discovered thata dopamine D₂ receptor antagonist such as domperidone may also cause anincrease in feed intake in the mammal resulting in weight increases.

Other objects, features and aspects of the present invention arediscussed in greater detail below.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

It is to be understood by one of ordinary skill in the art that thepresent discussion is a description of exemplary embodiments only, andis not intended as limiting the broader aspects of the presentinvention, which broader aspects are embodied in the exemplaryconstruction.

The present invention is generally directed to various processes andmethods for promoting and stimulating follicular growth and ovulation,for preparing a mammal for parturition, and for promoting andstimulating udder development and lactation. The process of the presentinvention can be used to treat anestrous mammals, agalactic mammals, andmore generally any mammal experiencing problems during the reproductivecycle. The process of the present invention can also be used tomanipulate and control ovulation and lactation. For instance, in mammalsthat only ovulate seasonally, the present invention can be used topromote ovulation at times when ovulation would not normally occur.

In general, the objects and advantages of the present invention areachieved by administering to a female mammal a composition containing adopamine D₂ receptor antagonist. A D₂ receptor antagonist should bechosen but does not substantially cross the blood brain barrier in orderto ensure that the mammal does not suffer any adverse behavioral orneurological side effects. For instance, in a preferred embodiment, thedopamine D₂ receptor antagonist is domperidone.

Although unknown, it is believed that domperidone ties up receptor cellsin the anterior pituitary and other places in the body preventingvarious chemical agents, such as dopamine, from binding to the receptorcells and altering the release of hormones throughout the body. Byaltering the effects of dopamine and other similar agents, domperidoneallows the anterior pituitary and other glands of the body to secretehormones necessary for ovulation, parturition, and lactation as will bedescribed in greater detail hereinafter.

As discussed above, one embodiment of the present invention is directedto a process for stimulating and promoting follicular growth andovulation. The process can be used to treat anestrous mammals, to causea mammal to ovulate out of season, or to otherwise control whenovulation occurs.

The process of the present invention can be used to treat any mammal,but is particularly applicable to livestock. For instance, many problemshave been experienced in attempting to get horses to breed. Further,mares only ovulate and fall into heat during particular times of theyear. The process of the present invention cannot only be used to treathorses that experience problems ovulating but can also be used to breedhorses during times of the year when it was not before possible.

According to the present invention, follicular growth and ovulation ispromoted by administering to a mammal a dopamine D₂ receptor antagonist.In one preferred embodiment, the dopamine D₂ receptor antagonist isdomperidone. The D₂ receptor antagonist can be taken orally by themammal or can be injected subcutaneously.

In one embodiment, when using domperidone, it has been found thatovulation is promoted when the domperidone is taken orally by a mammalin an amount from about 0.2 mg/kg (mg of domperidone per kg of bodyweight) to about 3.3 mg/kg. At concentrations greater than 3.3 mg/kg, nofurther benefits have been observed. Thus far, the best results havebeen obtained when domperidone has been taken orally at a concentrationof about 0.55 mg/kg.

If the domperidone is injected subcutaneously into the mammal, thedosages listed above can be reduced to about 40% of the oral dose. Thus,if injected into a mammal, domperidone can be administered at aconcentration of from about 0.08 mg/kg to about 1.32 mg/kg, with apreferred concentration of about 0.22 mg/kg.

Ovulation is the process by which an egg is discharged from a follicleof an ovary and is released into the fallopian tube and the uterus. Moreparticularly, in mammals, as eggs mature in the ovary, the eggs aresurrounded by a layer of follicular cells creating a fluid filledfollicle. As the egg reaches maturity, the fluid filled follicle bulgesfrom the surface of the ovary. Stimulated by a hormone, ovulation occurswhen the follicle ruptures, releasing the egg.

Ovarian cycles are initiated and controlled by a variety of hormonessecreted throughout the body. Specifically, these hormones includefollicle stimulating hormone (FSH) which is secreted by the pituitarygland and which stimulates follicular and egg growth. Luteinizinghormone (LH), which is also released from the pituitary gland,stimulates the follicle to secrete estrogen which causes the walls ofthe uterine to thicken. LH also triggers ovulation causing the follicleto rupture.

The levels and frequency of release of these hormones can be altered inthe body by various chemical agents such as dopamine. Although unknown,it is believed that the D₂ receptor antagonists of the presentinvention, such as domperidone, neutralize the effects of dopamine andother related chemical agents. By administering to a mammal a D₂receptor antagonist, LH and FSH can be released by the body withoutinhibition causing ovulation to occur.

Besides promoting ovulation, the present invention is also directed to aprocess for preparing a mammal for parturition. This process is fortreating mammals and particularly livestock that have problems givingbirth once pregnant.

Parturition is stimulated in a mammal according to the present inventionby administering to the mammal a composition containing a dopamine D₂receptor antagonist. For instance, in one embodiment, the compositioncan contain domperidone. Once administered to the mammal, it is believedthat the composition neutralizes the effects of dopamine and othersimilar chemical agents from altering the release of hormones thatprepare a mammal for giving birth. Thus, the composition of the presentinvention allows the body to secrete hormones that may affect cervicaldilation and general broodiness.

By administering the composition to pregnant mammals, the mammal is morelikely to give birth on time. The composition also promotes naturalbirths and prevents against having to deliver the offspring byC-sections. The treatment not only protects the unborn offspring duringdelivery but also protects the pregnant mother from being harmed duringbirth.

In order to promote normal parturition, in one embodiment, a pregnantmammal can be orally fed domperidone at a concentration of from about0.2 mg/kg of body weight to about 3.3 mg/kg. In one preferredembodiment, the oral dosage can be about 1.1 mg/kg.

When injected subcutaneously into the mammal, domperidone has been foundto produce effective results at concentrations of from about 0.08 mg/kgto about 1.32 mg/kg, with best results being obtained at about 0.44mg/kg. Amounts greater than 1.32 mg/kg can be administered to the animalwithout any adverse side effects. Additional benefits, however, have notbeen observed at higher dosage levels.

Whether administered orally or subcutaneously, treatments of the D₂receptor antagonist administered to the mammal can begin at any timeduring the pregnancy. For larger livestock such as cattle and horses,the treatment should begin about fifteen to twenty days prior to theexpected birth date.

A further embodiment of the present invention is directed to a processfor promoting udder development and lactation in female mammals. Theprocess can be used to prevent or treat agalactia or any other ailmentsregarding the low level or non-production of milk. For instance,lactation problems have been particularly observed in mares that haverecently given birth. After giving birth, many mares either fail toproduce milk or do not produce enough milk to adequately nurture thefoal. When this occurs, the foal must be bottle fed or fed in some othermanner which significantly adds to the expense of raising the livestock.

The process of the present invention can be used in these circumstancesto stimulate or increase milk production in non-milking mares and othermammals. Further, the process can be used simply to increase milkproduction without any adverse effects. For instance, the process of thepresent invention can also be used to increase the quantity of milkobtained from cows for human consumption.

Lactation is stimulated and promoted according to the present inventionby administering to mammals a composition containing a dopamine D₂receptor antagonist. For instance, the composition can containdomperidone in an amount sufficient to stimulate milk production.

In one embodiment, milk production was stimulated in horses by orallyadministering to the horses domperidone in a concentration of from about0.2 mg/kg of body weight to about 3.3 mg/kg of body weight, andparticularly at a concentration of about 1.1 mg/kg. At oral dosagesgreater than 3.3 mg/kg, no further beneficial results were observed.

Domperidone can also be administered to the animal subcutaneously. Ifinjected into the mammal, about 40% of the dosage amounts given abovecan be used. Thus, when injected subcutaneously, the domperidoneconcentration can be from about 0.08 mg/kg to about 1.32 mg/kg.

Although unknown, it is believed that the dopamine D₂ receptorantagonist, such as domperidone, influences hormonal levels within theanimal. Domperidone is believed to alter hormone levels by neutralizingthe effect of dopamine-like agents that prevent particular hormones frombeing secreted. With respect to lactation, it is believed that thedopamine D₂ receptor antagonist increases the levels of progesterone,estrogen and prolactin within the body of the mammal. These hormones arebelieved to be primarily responsible for promoting udder development andlactation.

Besides promoting ovulation, preparing a mammal for parturition, andstimulating lactation, it has also been unexpectedly discovered that thecomposition of the present invention can cause a mammal to increase itsfeed intake and thus gain weight faster. This process is particularlybeneficial in raising livestock for human consumption.

In order to increase feed intake according to the present invention, adopamine D₂ receptor antagonist, such as domperidone, is administered toa mammal. The treatment can be given to the mammal orally orsubcutaneously. If domperidone is used and administered orally, thedomperidone should be fed to the mammal at a concentration of from about0.2 mg/kg of body weight to about 3.3 mg/kg of body weight andparticularly at about 1.1 mg/kg. If domperidone is injected into themammal, the dosage should be from about 0.08 mg/kg to about 1.32 mg/kg.

At the present time, it is unknown why domperidone causes increases infeed intake. It is believed, however, that domperidone may stimulatefeed intake by increasing levels of the hormone prolactin in the body ofthe mammal. It may also be possible that domperidone causes levels ofhormones to be altered that firm up the gut of the mammal. If themuscles of the gut were to be stimulated, then food passage may increasein the gut allowing the animal to eat more.

In general, in delivering an effective dosage of a dopamine D₂ receptorantagonist to a mammal according to the present invention, variousvehicles may be used. For instance, when taken orally, the D₂ receptorantagonist may be combined with a feed or feed supplement material asthe carrier. If injected, the drug may be mixed with any suitablecarrier. Additionally, the D₂ receptor antagonist, such as domperidone,may be added to salt blocks or mineral blocks during casting or mixeddirectly into feed. Further, various other administration techniqueswell known in the art may be employed. It is to be understood that thepresent invention is not to be limited to any particular vehicle.

It also should be appreciated that although the above description andfollowing examples relate primarily to livestock such as horses andcattle, it is believed that the drug will work as described with anymammal. For instance, although untested at the present time, it isbelieved that a dopamine D₂ receptor antagonist that does notsubstantially cross the blood brain barrier such as domperidone may beadministered to humans for promoting ovulation, facilitating childbirth,or stimulating lactation.

The present invention may be better understood with reference to thefollowing examples.

EXAMPLE NO. 1

The following tests were performed in order to demonstrate the abilityof domperidone to stimulate and promote ovulation in mares.

Ten mares were fed a composition containing domperidone at aconcentration of 0.55 mg/kg of body weight. The composition wasadministered daily. Specifically, the domperidone was mixed withmolasses and fed to the mares with a 5 cc syringe. Nine additional mareswere used as a control. These mares were fed the molasses carrier notcontaining any domperidone.

Of importance, the treatments were carried out in January and Februaryduring a time when mares typically do not ovulate. The following resultswere obtained:

TABLE 1 Effect of Domperidone on Follicular Growth and Ovulation No. ofDays Treated with No. of of Treatment Test Domperidone Days of Date ofBefore No. at .55 mg/kg Treatment Ovulation Ovulation 1 No 45 d/novulate d/n ovulate 2 No 45 d/n ovulate d/n ovulate 3 No 45 d/n ovulated/n ovulate 4 No 25 Feb. 26 25 5 No 45 d/n ovulate d/n ovulate 6 No 45d/n ovulate d/n ovulate 7 No 45 d/n ovulate d/n ovulate 8 No 37 Mar. 1037 9 No 45 d/n ovulate d/n ovulate 10 Yes 18 Feb. 9  18 11 Yes 15 Feb.6  18 12 Yes 21 Feb. 12 21 13 Yes 17 Feb. 8  17 14 Yes 24 Feb. 15 24 15Yes 14 Feb. 5  14 16 Yes 16 Feb. 7  16 17 Yes 22 Feb. 13 22 18 Yes 45d/n ovulate d/n ovulate 19 Yes 19 Feb. 10 19

As shown above, only two of the control mares ovulated. In comparison,nine of the ten mares treated with domperidone ovulated. Also ofsignificance, the treated mares ovulated during the early part ofFebruary. No neurological side effects were observed in any of the marestreated with domperidone during the study.

EXAMPLE NO. 2

The following tests were performed to demonstrate the ability ofdomperidone to prepare a mammal for parturition and to stimulate udderdevelopment and lactation.

Twelve known agalactic mares who were either pregnant or had just givenbirth were treated with domperidone. The domperidone was administeredorally at a dosage of 1.1 mg/kg of body weight per day. All of the marestreated were not suffering from fescue toxicosis. The following resultswere obtained:

TABLE 2 Effect of Domperidone on Preparation for Parturition, UdderDevelopment and Lactation In Mares Days Before (−) Days Before (−) WasMare or After Expected or After Expected Mare's Udder Mare's UdderLactating Did Mare Foaling Dosing Was Foaling that Development BeforeDevelopment After Normally Have A Test No. Initiated Mare FoaledTreatment Began Treatment Began After Foaling? Live Foal? 1  +5 +12 Very Little Dripping Milk 5th Day Yes Yes of Treatment 2 −28 −1 VeryLittle Increased Weekly Yes Yes 3 No data +8 No Development After 2Days, Made Yes Yes Udder Sack 4  +6 +15  Very Little Developed SlowlyBut Yes Yes Natural 5  +4 +14  Virtually No Udder Developed AdequatelyNo. but drug Yes helped some 6 −21  0 Normal Normal Yes Yes 7  +5 Nodata Incomplete Small Udder Developed As Yes Yes Udder Soon As TreatmentStarted 8 −24 −3 No Development Very Slight Yes Yes Development 9 Nodata +3 Minimal Gradual Development Yes Yes 10  −13 No data Slight Base;No Filling Normal Development Yes Yes of Teat 11  −20 −3 No DevelopmentNo Response Yes Yes 12  −10 −2 None to Minimal Immediate Yes YesDevelopment After Treatment

EXAMPLE NO. 3

It has also been unexpectedly discovered that treating a mammal with aD₂ receptor antagonist, such as domperidone, increases feed intake. Thefollowing results demonstrate this phenomenon.

Ten quarter horse mares were housed in individual pens and fed astandard feed concentrate weighing 0.5% of each mares' initial bodyweight at approximately 8:00 A.M. each day during the study. Inaddition, hay was fed to the mare ad libitum each day. During the night,the mares were placed in a dry lot having no access to food.

After seven days on the above feed schedule (control), the mares wereorally fed at 8:00 A.M. each day domperidone at a dosage of 1.1 mg/kg ofbody weight. The domperidone was fed to the mares in a molasses carrier.During treatment with domperidone, the mares were fed the concentratefeed and hay in the same manner as during the control period.Domperidone was fed to the mares for two weeks. The following resultswere obtained:

TABLE 3 Effect of Domperidone On The Daily Feed Intake of Mares Avg. HayAvg. Hay Initial Consumption Consumption Body Before After Mare WeightConcentrate Treatment Treatment ID (lbs) Feed (lbs) (lbs) (lbs) 1 10255.1 11.2 13.0 2  980 4.9 10.3 12.2 3 1110 5.6 12.2 14.1 4  900 4.5 11.113.2 5 1050 5.3 12.0 14.1 6 1000 5.0 11.0 14.2 7  980 4.9  9.8 12.3 81010 5.1 11.0 13.5 9 1100 5.5 12.5 15.0 10   950 4.8 10.2 12.1

As shown above, daily hay consumption increased for each of the tenmares after treatment with domperidone began.

These and other modifications and variations to the present inventionmay be practiced by those of ordinary skill in the art, withoutdeparting from the spirit and scope of the present invention, which ismore particularly set forth in the appended claims. In addition, itshould be understood that aspects of the various embodiments may beinterchanged both in whole or in part. Furthermore, those of ordinaryskill in the art will appreciate that the foregoing description is byway of example only, and is not intended to limit the invention sofurther described in such appended claims.

What is claimed:
 1. A method for promoting parturition in animalscomprising the step of: administering to a pregnant female animal notsuffering from fescue toxicosis a composition comprising domperidone,said domperidone being administered to said pregnant animal in an amountsufficient to promote parturition.
 2. A method as defined in claim 1,wherein said domperidone is administered to said pregnant animal in anamount from about 0.08 mg to about 3.3 mg per kilogram weight of saidweight.
 3. A method as defined in claim 1, wherein said composition isadministered orally.
 4. A method as defined in claim 1, wherein saidcomposition is administered subcutaneously.
 5. A method as defined inclaim 3, wherein said composition is administered orally to saidpregnant animal in an amount from about 0.2 mg to about 3.3 mg perkilogram weight of said animal.
 6. A method as defined in claim 4,wherein said composition is administered subcutaneously to said pregnantanimal in an amount from about 0.08 mg to about 1.32 mg per kilogramweight of said animal.
 7. A method as defined in claim 1, wherein saidpregnant animal is an animal selected from the group consisting of amare or a cow.